A region of the SARS-CoV-2 spike protein functionally interacts with the human alpha7 nicotinici receptor

CHRESTIA, J.F.; OLIVEIRA, A.S.F.; MULHOLLAND, A.J.; GALLAGHER, T.; BERMÚDEZ, I.; BOUZAT, C.B.

Congreso Virtual

Congreso; XLIX Reunión Anual de la Sociedad Argentina de Biofísica; 2021

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The binding of the viral spike protein (S) to angiotensinconverting enzyme 2 in host cells is crucial for infection. The S protein has been suggested to interact with nicotinic acetylcholine receptors (nAChRs), and their contribution to the COVID-19 inflammatory pathophysiology has been proposed. Alpha7 is an interesting candidate target because it is present in neuronal and non-neuronal cells, and it has neuroprotective and anti-inflammatory actions. By whole-cell and single-channel recordings we revealed that the Y674-R685 region of the S protein shows a direct functional interaction with human alpha7 nAChR. The S fragment exerts a dual effect, acting as a low-efficacy agonist and a non-competitive antagonist. In agreement with molecular dynamics simulations showing stable binding of this region to the ACh binding pocket, the S fragment activates alpha7, but only in the presence of a potentiator, supporting its action as a very low-efficacy agonist. In addition, it allosterically inhibits alpha7 responses elicited by ACh, which may result in the predominant effect. This study provides unequivocal evidence supporting a functional alpha7-S protein interaction, which may play a role in infectivity and/or disease progression and may be explored for new therapeutic opportunities.